Jerry W Cubbage

Publications (5)15.3 Total impact

• Article: Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

  Robert O Hughes, D Joseph Rogier, E Jon Jacobsen, John K Walker, Alan Macinnes, Brian R Bond, Lena L Zhang, Ying Yu, Yi Zheng, Jeanne M Rumsey, [......], David L Brown, Brad A Acker, Todd M Maddux, Mike B Tollefson, Brent V Mischke, Dafydd R Owen, John N Freskos, John M Molyneaux, Alan G Benson, Rhadika M Blevis-Bal
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  ABSTRACT: We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
  Journal of Medicinal Chemistry 03/2010; 53(6):2656-60. · 4.80 Impact Factor
• Article: Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one.

  Robert O Hughes, John K Walker, D Joseph Rogier, Steve E Heasley, Rhadika M Blevis-Bal, Alan G Benson, E Jon Jacobsen, Jerry W Cubbage, Yvette M Fobian, Dafydd R Owen, [......], Brad A Acker, Todd M Maddux, Mike B Tollefson, Joseph B Moon, Brent V Mischke, Jeanne M Rumsey, Yi Zheng, Alan MacInnes, Brian R Bond, Ying Yu
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  ABSTRACT: We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
  Bioorganic & medicinal chemistry letters 08/2009; 19(17):5209-13. · 2.65 Impact Factor
• Article: Investigation of aminopyridiopyrazinones as PDE5 inhibitors: Evaluation of modifications to the central ring system.

  Robert O Hughes, John K Walker, Jerry W Cubbage, Yvette M Fobian, D Joseph Rogier, Steve E Heasley, Rhadika M Blevis-Bal, Alan G Benson, Dafydd R Owen, E Jon Jacobsen, [......], Todd M Maddux, Mike B Tollefson, Jennifer M Williams, Joseph B Moon, Brent V Mischke, Jeanne M Rumsey, Yi Zheng, Alan Macinnes, Brian R Bond, Ying Yu
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  ABSTRACT: Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
  Bioorganic & medicinal chemistry letters 07/2009; 19(15):4092-6. · 2.65 Impact Factor
• Article: Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.

  Dafydd R Owen, John K Walker, E Jon Jacobsen, John N Freskos, Robert O Hughes, David L Brown, Andrew S Bell, David G Brown, Christopher Phillips, Brent V Mischke, [......], Margarita Rodriquez-Lens, Jerry W Cubbage, Radhika M Blevis-Bal, Alan G Benson, Brad A Acker, Todd M Maddux, Michael B Tollefson, Brian R Bond, Alan Macinnes, Yung Yu
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  ABSTRACT: A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
  Bioorganic & medicinal chemistry letters 07/2009; 19(15):4088-91. · 2.65 Impact Factor
• Article: A catch-and-release strategy for the combinatorial synthesis of 4-acylamino-1,3-thiazoles as potential CDK5 inhibitors.

  Scott D Larsen, Carl F Stachew, Paula M Clare, Jerry W Cubbage, Karen L Leach
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  ABSTRACT: Two-dimensional libraries of 4-acylamino-1,3-thiazoles 9 were prepared via Curtius rearrangement of 1,3-thiazole-4-carbonyl azides 6, trapping of the intermediate isocyanates with oxime resin, and thermal regeneration of the isocyanates from the washed resin in the presence of nucleophiles. Several compounds proved to be selective inhibitors of CDK5/p25 versus the closely homologous CDK2/cyclin A enzyme, with the best analogue (43) possessing over 100-fold selectivity.
  Bioorganic & Medicinal Chemistry Letters 11/2003; 13(20):3491-5. · 2.55 Impact Factor